Cyclophosphamide is effective therapy for murine lupus. MRL-lpr/lpr mice treated with corticosteroids from 3 months of age did not achieve significantly prolonged survival. Others have reported that tumor necrosis factor alpha (TNF) deficiency is a fundamental defect in murine lupus and that replacement therapy is very effective in preventing disease. We have treated BXSB males, MRL-lpr/lpr mice of both sexes and (NZB x NZW)Fl mice with TNF after the onset of disease manifestations. Such therapy was of modest benefit. Lymphadenopathy was reduced in MRL-lpr/lpr mice but survival was not prolonged in any of the strains. Increased survival was observed when younger mice were given prophylactic therapy. In vivo administration of mel-14, an antibody to a molecule critical to lymphocyte lymph node homing, led to a marked decrease in lymphadenopathy in MRL-lpr/lpr mice.